ABSTRACT Molecular imaging (MI) originated in the need to better understand the fundamental molecular pathways inside organisms in a noninvasive manner. Over the past two decades, two factors have acted in concert to fuel the ascent of molecular imaging in both the laboratory and the clinic: (1) an increased understanding of the molecular mechanisms of disease and (2) the continued development of in vivo imaging technologies, ranging from improved detectors to novel labeling methodologies. We have established a vibrant and state-of-the-art laboratory-based translational research program. The Lewis lab portfolio is situated at the intersection of various disciplines ? radiochemistry, cancer biology, chemistry, pharmacology and engineering. Our program has already demonstrated that our work is not just to generate an ?image? but also to non-invasively and quantitatively measure target biology within a cancer. Even with the extensive preclinical advances in cancer imaging that we have accomplished and the unparalleled visualization of cancer biology we have achieved, our ability to translate our findings cannot be understated. Our program has excelled in the clinical translation of new imaging agents, providing new insights into cancer biology in humans. In the realms of this R35 we plan to focus on three main areas of discovery: (1) Can our successful imaging agents be transformed into theranostic agents with the ability to quantify the target through non-invasive imaging while providing concomitant lethality? (2) How can our theranostic agents be optimally deployed to quantitatively and non-invasively interrogate and treat tumor heterogeneity? (3) Following conventional and/or novel targeted therapies, can we image cancer-specific pathways to provide immediate and real-time predictors of response? We will exploit recent findings and novel methods to answer these questions, using an integrated set of imaging, chemical, genomic and cancer biology approaches. As such, the questions posed above will be of more general relevance and will allow us to address concepts related to the interactions between imaging, therapy, and response.